Medical treatment for people with primary sclerosing cholangitis

Background

Primary sclerosing cholangitis is a disease that affects the bile ducts. Bile ducts are tubes that transport the bile produced by liver cells. Primary sclerosing cholangitis is a relatively uncommon disease, with 1 in 10,000 people affected. It is more common among men, and most people receive the diagnosis at between 30 and 50 years of age. Primary sclerosing cholangitis can lead to liver damage, liver failure, and bile duct cancer, and it decreases a person's longevity. Various medical treatments for primary sclerosing cholangitis have been tested. The best way to treat patients with primary sclerosing cholangitis remains unclear. We sought to resolve this issue by searching for studies conducted to explore this topic. We included all randomised clinical trials whose results were reported until February 2017. We included only trials in which participants had not undergone liver transplantation before participating in the trial. Apart from using standard Cochrane methods, which allow comparison of only two treatments at a time (direct comparison), we planned to use an advanced method (network meta-analysis) that would allow comparison of many different individual treatments as reported by research trials. However, because of the nature of the available information, we could not determine whether results of the network meta-analysis were reliable. So, we used standard Cochrane methods instead.

Study characteristics

We identified 22 randomised clinical trials with a total of 2211 participants that met our inclusion criteria. Participants in these trials were randomised to 13 different treatments. In most trials, placebo (dummy treatment) was provided as one of the treatments. Trials applied few restrictions apart from confirmation of primary sclerosing cholangitis, evidence of bile stagnation, which is an early marker of primary sclerosing cholangitis, absence of liver failure, and absence of cancer. However, only 11 trials (706 participants) provided the information that we sought. The remaining trials, which were conducted in people with primary sclerosing cholangitis, compared different treatments but did not report important information on deaths, complications, health-related quality of life, liver failure, liver transplantation, or cancer. Participants in most of these trials were followed-up only for three months to three years. Only three trials followed-up trial participants for longer than three years.

Source of funding: Fifteen trials reported their source of funding; three of these were funded by parties without vested interest in results of the trial, and 12 were funded in part or in full by drug companies.

Key results

Differences in important clinical benefits such as reduction in mortality (deaths) at maximal follow-up, improvement in health-related quality of life, reduction in the requirement for liver transplantation, or reduction in development of cholangiocarcinoma were imprecise in all comparisons. Other important clinical benefits such as incidence proportion of all malignancies, colorectal cancer, liver decompensation, time to liver decompensation, and time to liver transplantation and requirement for cholecystectomy were not reported in any trial in a format that could be analysed to allow comparison between different treatments. No evidence currently suggests that any medical treatment for primary sclerosing cholangitis is effective. An urgent need exists to identify an effective medical treatment for patients with primary sclerosing cholangitis by performing additional well-designed randomised clinical trials.

Quality of evidence

The overall quality of evidence was very low, and all trials were judged to be at high risk of bias, which means that wrong conclusions may overestimate benefits or underestimate harms of one treatment or another because of the way the trials were conducted.

Authors' conclusions: 

Evidence is currently insufficient to show differences in effectiveness measures such as mortality, health-related quality of life, cirrhosis, or liver transplantation between any active pharmacological intervention and no intervention. However, trials were at high risk of bias and included small numbers of participants, had short follow-up periods, and reported few clinical outcomes. An urgent need exists to identify an effective medical treatment for primary sclerosing cholangitis through well-designed RCTs with adequate follow-up that aim to identify differences in outcomes important to people with primary sclerosing cholangitis.

Read the full abstract...
Background: 

Primary sclerosing cholangitis is a chronic cholestatic liver disease that is associated with both hepatobiliary and colorectal malignancies, which can result in liver cirrhosis and its complications. The optimal pharmacological treatment for patients with primary sclerosing cholangitis remains controversial.

Objectives: 

To assess the comparative benefits and harms of different pharmacological interventions in people with primary sclerosing cholangitis by performing a network meta-analysis, and to generate rankings of available pharmacological interventions according to their safety and efficacy. Given that it was not possible to assess whether potential effect modifiers were similar across comparisons, we did not perform the network meta-analysis but instead used standard Cochrane methods.

When trials begin to provide an adequate description of potential effect modifiers, we will attempt to conduct network meta-analysis.

Search strategy: 

We searched CENTRAL, MEDLINE, Embase, Science Citation Index - Expanded, the WHO International Clinical Trials Registry Platform, and randomised controlled trials registers until February 2017 to identify randomised clinical trials (RCT) on pharmacological interventions for primary sclerosing cholangitis.

Selection criteria: 

We included only RCTs, irrespective of language, blinding, or publication status, in which participants were given a diagnosis of primary sclerosing cholangitis. We excluded trials that included previously liver-transplanted participants. We considered any of various pharmacological interventions compared with one other or with placebo. We excluded trials that compared different doses of various pharmacological interventions or that reported different treatment durations, except for ursodeoxycholic acid (UDCA). As UDCA is the drug most commonly investigated for primary sclerosing cholangitis, we performed a second analysis in which we stratified the dose of UDCA.

Data collection and analysis: 

We calculated the odds ratio and the rate ratio with 95% confidence intervals (CIs) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE.

Main results: 

We identified 22 RCTs in which 1211 participants were randomised to 13 different interventions. Most were placebo-controlled trials. Trials had few restrictions apart from an established diagnosis of primary sclerosing cholangitis, evidence of cholestasis, absence of decompensated liver disease, and absence of malignancy. However, some trials included symptomatic participants only, and others included both symptomatic and asymptomatic participants. A total of 11 RCTs (706 participants) provided data for one or more outcomes. The period of follow-up ranged from three months to three years in most trials. Only three trials reported follow-up longer than three years. Investigators found no evidence of differences in important clinical benefits such as reduction in mortality at maximal follow-up and improvement in health-related quality of life.

Primary outcomes
Mortality: Effect estimates: colchicine versus placebo: odds ratio 0.44, 95% CI 0.04 to 5.07, participants = 84, one trial; penicillamine versus placebo: odds ratio 1.18, 95% CI 0.39 to 3.58, participants = 70, one trial; steroids versus placebo: odds ratio 3.00, 95% CI 0.10 to 90.96, participants = 11, one trial; ursodeoxycholic acid versus placebo: odds ratio 1.51, 95% CI 0.63 to 3.63, participants = 348, two trials, I2 = 0%; vancomycin versus placebo: not estimable because no events in either group, participants = 29, one trial.

Serious adverse events (proportion): Effect estimates: infliximab versus placebo: odds ratio not estimable (because of zero events in both arms), participants = 7, one trial; steroids versus placebo: odds ratio 20.00, 95% CI 0.93 to 429.90, participants = 11, one trial; vancomycin versus placebo: not estimable because no events in either group, participants = 29, one trial.

Serious adverse events (number): Effect estimates: infliximab versus placebo: rate ratio 0.80, 95% CI 0.02 to 40.44, participants = 7, one trial; penicillamine versus placebo: rate ratio 13.60, 95% CI 0.78 to 237.83, participants = 70, one trial; steroids versus placebo: rate ratio 3.32, 95% CI 0.71 to 15.62, participants = 11, one trial.

Adverse events (proportion): Effect estimates: steroids versus placebo: odds ratio 20.00, 95% CI 0.93 to 429.90, participants = 11, one trial; ursodeoxycholic acid versus placebo: odds ratio 1.22, 95% CI 0.68 to 2.17, participants = 198, one trial; vancomycin versus placebo: not estimable because no events in either group, participants = 29, one trial.

Adverse events (number): Effect estimates: cyclosporin versus placebo: rate ratio 2.64, 95% CI 0.99 to 7.03, participants = 26, one trial; steroids versus placebo: rate ratio 3.32, 95% CI 0.71 to 15.62, participants = 11, one trial; ursodeoxycholic acid plus metronidazole versus ursodeoxycholic acid: rate ratio 2.36, 95% CI 0.98 to 5.71, participants = 71, one trial.

Health-related quality of life: ursodeoxycholic acid versus placebo: mean difference 1.30, 95% CI -5.61 to 8.21, participants = 198, one trial (Short Form (SF)-36 General Health Scale).

Secondary outcomes
Studies provided no evidence of differences in clinical benefits such as a reduction in the requirement for liver transplantation or a reduction in the incidence proportion of cholangiocarcinoma. One small trial (29 participants) comparing vancomycin versus placebo reported no malignancies, no liver decompensation, and no liver transplantation in either group after a very short follow-up period of 12 weeks after treatment. None of the remaining trials clearly reported other clinical benefits such as decreased development of all malignancies, colorectal cancer, liver decompensation, time to liver decompensation, time to liver transplantation, or requirement for cholecystectomy to allow comparisons between different interventions.

Source of funding: Fifteen trials reported the source of funding; three were funded by parties without vested interest in results of the trial, and 12 were funded in part or in full by drug companies.

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